PROJECT SUMMARY/ABSTRACT Cerebral aneurysms affect up to 5% of the population. When cerebral aneurysms rupture, they cause devastating subarachnoid hemorrhage with greater than 50% mortality. Currently, the only treatments that prevent rupture are prophylactic cranial or endovascular surgery which are risky. A gap in knowledge persists about the pathophysiology of aneurysm formation, growth, and rupture. The long-term goal is to improve understanding of the mediators and mechanisms of cerebral aneurysm formation and rupture, and thereby identify therapeutic targets for the development of novel therapies. Our laboratory studies this problem from two different approaches: 1) improve aneurysm endovascular devices to achieve complete aneurysm healing, and 2) improve our understanding of what causes aneurysms to develop and grow. We recently found chemokine (C-X-C motif) ligand 1 (CXCL1) antagonism achieves both: we found CXCL1 antagonism significantly inhibits mouse cerebral aneurysm formation (13.3 versus 66.7%; P =0.0078), and in mouse carotid aneurysms treated with coiling, CXCL1 antagonism, significantly improves intrasaccular aneurysm coil occlusion and healing (preliminary data). Improving our understanding of the mechanisms is intriguing because this could translate to treating patients' aneurysms with coiling, and supplementing with a drug that facilitates intrasaccular aneurysm healing and by a separate mechanism inhibits further cerebral aneurysm growth. Our central hypothesis: CXCL1 antagonism promotes intrasaccular aneurysm occlusion and healing with coiling and protects against cerebral aneurysm formation by modulating the macrophage and neutrophil-mediated site-specific inflammatory response. We will test our central hypothesis with the following aims in this Early Established Investigator application: 1) Demonstrate CXCL1 is necessary for aneurysm rupture. CXCL1 antagonism improves aneurysm healing; 2) Demonstrate IL17 induces CXCL1-mediated aneurysm formation and rupture and CXCL1 inhibition of aneurysm coil healing; and 3) Demonstrate infiltrating macrophages and neutrophils mediate CXCL1-induced aneurysm formation and rupture and CXCL1 inhibition of aneurysm coil healing. The proposal is conceptually innovative in that we will propose a novel link between IL17, CXCL1, neutrophils and macrophages and precisely define their roles as mediators in cerebral aneurysm formation and rupture. Furthermore, the proposed studies are the first to investigate a mediator that both promotes intrasaccular aneurysm healing and protects against cerebral aneurysm growth and rupture. The significance of this work is the potential identification of novel targets with direct translational benefit.